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My question concerns the meaning and validity of clearance and
distribution volume (all) calculations under three conditions. First,
after a single dose (trivial - I only include it for completeness).
Second, after repeated intravenous doses (e.g. three identical
intravenous doses QD with calculations done on the last dose) for
which steady-state is not achieved. Third, after repeated intravenous
doses at which steady-state is assumed to have been reached. The
obvious difficultly to me is that dose after repeated injections may
no longer be the administered dose since there could be carry-over
from the next to last dose. Perhaps there are other considerations I
am not aware of. Thank you in advance for your help.
Richard Knapp
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Dear Richard,
I think you can use the equations for multiple doses.
Carlos Hoyo
Farma, Cinvestav
Mexico
--
Saludos, -- CapitanMacintosh.-at-.gmail.com Dr. Carlos Hoyo Vadillo
Farmacologia Cinvestav
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The following message was posted to: PharmPK
Richard,
If you'd like to send the data, I'd be happy to fit all three dosage
regimens simultaneously with a nonlinear model using GastroPlus and
sent you
the results. It would help, of course, if you have some idea of how
the drug
is cleared - renal, metabolism, both, etc.
It should only take a few minutes.
Best regards,
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
E-mail: walt.-at-.simulations-plus.com
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Richard,
Clearance and volume exist without giving any dose. They are
parameters which are independent of the dosing scenario.
Phamacokinetic models take care of the carry over with repeated doses.
There are some special cases where these parameters depend on
concentration and thus on the dosing scenario but once again PK models
can be adapted to take care of this and describe the concs with
further parameters (e.g. Vmax and Km instead of clearance).
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
n.holford.at.auckland.ac.nz
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
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Dear Richard,
Think about principle of superposition. The following paper might be
of help:
Wenping Wang and S. Peter Ouyang. The Formulation of the Principle of
Superposition in the Presence of Non-Compliance and Its Applications
in Multiple Dose Pharmacokinetics. Journal of Pharmacokinetics and
Biopharmaceutics, Vol. 26, No. 4, 457 (1998)
Kind regards,
Dimiter T.
--
Dimiter Terziivanov, MD,PhD,DSc, Professor and Head,
Clinic of Clinical Pharmacology and Pharmacokinetics,
Univ Hosp "St. Ivan Rilski",
15 Acad. Ivan Geshov st, 1431 Sofia, Bulgaria
e-mail: dterziivanov.at.rilski.com; terziiv.-a-.yahoo.com
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